Induction of mitochondrial biogenesis enhances neurogenesis and cognitive recovery following ischaemic stroke

Abstract Purpose Stroke can cause severe cognitive impairment in patients. Recently, neurogenesis has been proposed as a potential approach to improve cognitive abilities after stroke. However, no effective treatment strategy currently exists for stimulating hippocampal neurogenesis to promote cognitive recovery. Therefore, this study investigated the mechanisms underlying the increase in hippocampal neurogenesis induced by mitochondrial biogenesis. Methods To achieve the objective, mice subjected to the global cerebral ischaemia (GCI) model via bilateral common carotid artery occlusion were used to investigate mitochondrial biogenesis in vivo through western blotting, transmission electron microscopy, and immunofluorescence staining. Hippocampal neurogenesis was assessed using immunofluorescence staining. Cognitive functions were evaluated using the open field test, novel object recognition, fear conditioning, and Morris water maze. In addition, an in vitro oxygen–glucose deprivation model served as a stroke analogue. Neurite outgrowth in primary neurons was quantified using immunofluorescence staining, while mitochondrial function parameters, including adenosine triphosphate, mitochondrial membrane potential, and reactive oxygen species, were measured using specific assay kits. Lentiviruses were used to manipulate mitochondrial biogenesis both in vivo and in vitro. Results We observed that the time course of mitochondrial biogenesis matched that of neurogenesis in the hippocampal dentate gyrus (DG) following GCI. Promoting mitochondrial biogenesis enhanced neurogenesis in the DG, lengthened neurites, and improved mitochondrial function, collectively alleviating cognitive deficits following stroke. Conversely, inhibition of mitochondrial biogenesis had the opposite effect. In addition, ubiquinol-cytochrome c reductase core protein 1 (UQCRC1) was identified as a crucial component of mitochondrial biogenesis. UQCRC1 knockdown impaired neurogenesis and cognitive abilities in mice. Conclusion This study highlights that mitochondrial biogenesis plays a pivotal role in neurogenesis within the hippocampal DG and may represent a promising strategy for treating cognitive impairment associated with ischaemic stroke. Graphical Abstract